Abstract Treatment of segmental large bone defects remains a significant clinical problem. Pre- vascularized large bone grafts capable of rapidly anastomosing with host vessel bed and integrating with native bone tissue would significantly advance currently available treatments. Addressing these issues is expected to overcome one of the stumbling blocks of tissue engineering and revolutionize the treatment of large bone defects. In this project, we propose to engineer a novel pre-vascularized bone graft substitute to repair large bone defects. The novel bone graft is comprised of a channeled, biodegradable calcium phosphate-polymer composite scaffold containing a cell-laden hydrogel (as a bone surrogate) and a flexible, suturable, antithrombotic, permeable polymer-based tissue engineered vessel graft (TEVG, as a blood vessel surrogate). The TEVG will be incorporated into the scaffold in a spatially controlled fashion. Our hypothesis is that the TEVG will facilitate and promote microvascularization across the scaffold, while allowing for surgical anastomosis to enable instant integration between the engineered bone graft and host tissue to repair large bone defects. To test our hypothesis, our team comprised of experts in biomaterials, bone tissue engineering, neovascularization, micro- surgery and orthopedic surgery, proposes the following aims:!Aim 1 is to develop a TEVG that facilitates host vascular integration. Aim 2 is to design and develop an instantly integrated, pre- vascularized bone graft substitute. Aim 3 is to determine the efficiency of a vascularized bone tissue construct prototype to enhance integration with host bone tissue, accelerate bone regeneration and restore functionality. The accomplishment of this project will revolutionize vascularized synthetic bone graft design, and pave the way for improved clinical treatments for large segmental bone defects. !